Diagnostic imaging has emerged in recent years as a superior technique for noninvasive clinical diagnosis of heart, brain, kidney and other organs and tissues in mammalian hosts. Nuclear magnetic resonance (NMR) analysis, or magnetic resonance imaging (MRI), in many instances, requires contrast enhancement to obtain useful images which delineate various aspects of the tissue, especially normal as contrasted with abnormal tissue.
The techniques of MRI or NMR imaging encompass the detection of certain atomic nuclei utilizing magnetic fields and radio-frequency radiation. It is similar in some respects to X-ray computed tomography (CT) in providing a cross-sectional display of the body organ anatomy with excellent resolution of soft tissue detail. In current use, the images produced constitute a map of the distribution density of protons and/or their relaxation times in organs and tissues. The MRI technique is advantageously non-invasive as it avoids the use of ionizing radiation.
The prior art discloses various techniques that can be employed for affecting an NMR signal in a host, of which a common technique is to introduce into the host a paramagnetic substance prior to NMR analysis which advantageously affects contrast, or selectively shifts the NMR signal. A large variety of compounds have found use in NMR and X-ray image analysis or as shift reagents.
New compounds with low toxicity in vivo, high relaxivity, tissue and pathology specificity, and sufficient tissue retention time but complete eventual clearance are being sought. The well known ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA) complexes with gadolinium (Gd) show low toxicity in vivo and rapid clearance rates but do not exhibit strong tissue specificity and long enough retention time, especially for myocardial tissue. Also their relaxivity decreases at high magnetic fields already being introduced into the industry. Accordingly, contrast enhancing agents with higher relaxivity, positive field profile, greater tissue specificity and sufficient tissue retention time in addition to low toxicity are needed. One approach has been to modify EDTA and DTPA to achieve these goals.
U.S. Pat. No. 4,647,447 reports chelating agents for NMR analysis which include EDTA derivatives and DTPA derivatives differing significantly from the present invention because they lack the lipophilic fatty acid moiety of the subject invention, and because of their inherently negative field profiles.
Several additional EDTA and DTPA derivatives are disclosed in U.S. Pat. Nos. 4,687,658; 4,687,659; 4,746,507; 4,804,529 and 4,822,594. Collectively, these patents report ester, amide and polysaccharide derivatives suitable for general MRI analysis but which, nevertheless do not have the fatty acid derivatives and positive field profiles of the present invention.
Fatty acids and fatty acid analogs have been reported to accumulate in myocardial tissue when administered as radiopharmaceuticals. U.S. Pat. No. 4,763,358 discloses that branched chain fatty acids have utility in cardiac imaging using radioactive iodine as the contrast moiety.
In a study of the biological distribution of chemical analogs of fatty acids and long chain hydrocarbons containing a strong chelating agent, Karesh, S.M. et al. (1977) J. Pharm. Sci 66: 225-228, describe radio-pharmaceutical cobalt (Co) and technicium (Tc) complexes wherein the alkyl end of a fatty acid molecule is covalently bound to a carboxyl group on the chelating agent, forming an ester derivative of the chelating agent. In contrast, the subject chelating agents are ester derivatives of the fatty acid and will therefore be more lipophilic due to the long, free alkyl chain then the-Karesh compounds which exhibit significant hydrophilic character due to the free carboxylic acid ends. Moreover, Karesh reports that the compounds under investigation studied were not sufficient biological analogs to act as tracers for fatty acid metabolism in the myocardium.
Accordingly, the present invention provides contrast enhancing agents for diagnostic image analysis which are lipophilic in nature because of a free hydrocarbon chain coupled via an ester linkage with a strong chelating agent, such as polyaminopolycarboxylic acid derivatives, especially EDTA and DTPA derivatives.